On her second patrol - from 31 December 1941-29 January 1942 - conducted between Manila and Surabaya, the submarine sank Kanko Maru on 10 January 1942. On her third war patrol - from 7 February-19 March - along the Malay Barrier and her fourth - from 15 April-6 June - in the Philippines, she failed to score (although she did make an unsuccessful torpedo attack on the unarmed Japanese hospital ship Takasago Maru on 26 April). [11]

On her sixth war patrol - from 22 January to 3 March 1943, she searched among the Kurile Islands on the Tokyo-Kiska traffic lanes. In sixteen attacks, she sank Tateyama Maru and two 35-ton sampans.

She departed Pearl Harbor on 18 March 1943 and, after topping off with fuel and provisions at Midway Island on 22 March, headed for the eastern coast of northern Honshū, Japan and was never heard from again. Pickerel was the first submarine to be lost in the Central Pacific area. She was stricken from the Naval Vessel Register on 19 August 1943.

Post-war analysis of Japanese records give conflicting suggestions about Pickerel's fate. The Japanese officially credit her with sinking Submarine Chaser Number 13 on 3 April and Fukuei Maru on 7 April, and give no official report of her destruction. Those records also describe an action off Shiramuka Lighthouse on northern Honshū on 3 April 1943 in which naval aircraft first bombed an unidentified submarine, then directed Shiragami and Bunzan Maru to the spot, where they dropped twenty-six depth charges. A large quantity of oil floated to the surface, which was often enough for Japanese ASW ships to believe their target was sunk. It is likely Pickerel's fuel oil bunkers leaked. Since there were several other ASW operations in the area in that period,[12] and Pickerel was the only American submarine in that area; one of these other attacks, sometime after 7 April, probably claimed her.